This application claims priority from German Application No. 198 22 912.7, filed on May 22, 1998, the subject matter of which is hereby incorporated herein by reference.
1. Field of the Invention
The present invention relates to a process for the preparation of compounds of the general formula I and their salts 
wherein
R1 may represent H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C2-C8)-alkoxyalkyl, (C1-C8)-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C3-C7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, N-bonded amino acid or peptide residue,
R2 may represent H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C2-C8)-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C3-C7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms,
R3 may represent H, ClCO, (C3-C8)-acyl, which may optionally be linear or branched, a C-bonded amino acid or peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl.
The invention relates also to novel intermediates of the general formulae V, IV and II and their salts 
wherein R1, R2, R3 are as defined above and R4 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkoxy, (C2-C8) alkenyloxy, which are optionally linear or branched and are optionally substituted by one or more halogen atoms, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, arylalkyloxy, such as benzyloxy, and R5 represents H, or R5 and R3 are bonded together via a Cxe2x95x90O group to form a ring, wherein in formula V, when R2 is H, R3 may not be H, and to the uses of those intermediates.
2. Background Information
The compounds that can be prepared by the process according to the invention and the novel intermediates are valuable intermediates for the production of biologically active substances. For example, 3-amino-2-oxo-pyrrolidines are preferably used as a structural unit for peptide mimetics, which are used as pharmaceuticals. In WO 94/22820, 3-amino-1-phenyl-2-oxo-pyrrolidines substituted at the phenyl ring, for example, are described as intermediates for thrombocyte aggregation inhibitors. Other biologically active compounds containing those xcex3-lactams have been studied by Kottirsch et al. (Bioorg. Med. Chem. Lett. 1993, 3, 1675). In other examples, they are used in highly potent neurokinin NK-2 receptor antagonists according to Deal et al. (J. Med. Chem. 1992, 35, 4195).
The majority of the processes used hitherto for the preparation of substituted 3-amino-2-oxo-pyrrolidines consist in first converting the corresponding open-chained methionine compounds into their sulfonium salts and cyclising the latter with strong bases in a suitable solvent. Friedinger et al. (J. Org. Chem. 1982, 47, 104-109) use for that purpose methyl iodide and sodium hydride, which is difficult to handle in a large-scale process. In U.S. Pat. No. 5,484,946, trimethylsulfonium or trimethylsulfoxonium salts are used for the alkylation instead of methyl iodide, which is readily volatile. The cyclisation is then carried out using potassium carbonate.
However, the main problem of those procedures, namely the unavoidable release from the methionine precursor of dimethyl sulfide, which is extremely strong-smelling, cannot be avoided in the process just mentioned either. Moreover, the necessary use of expensive aprotic polar solvents such as, for example, DMSO in the cyclisation with potassium carbonate appears to be a further disadvantage.
WO 94/22820 mentions a process in which racemic homoserine derivatives, which have been prepared starting from butyrolactone, are cyclised to pyrrolidones by means of triphenylphosphine and azodicarboxylic acid diesters. However, those reagents are not very suitable for use in an industrial process since they are relatively expensive. Moreover, the cyclisation in that variant yields a number of secondary products which are difficult and hence time-consuming and expensive to separate from the desired derivative (K. Nakajima et al. Peptide Chemistry 1983, 77-80).
Although L-homoserine is a naturally occurring amino acid, as yet there are known only a relatively small number of syntheses of homoserineamides, for example peptides, that start from homoserine. The reasons therefor are that homoserine and the corresponding N-acyl compounds very readily form the corresponding lactones under acid conditions (J. P. Greenstein, M. Winitz, xe2x80x9cChemistry of the Amino Acidsxe2x80x9d, Wiley, N.Y. 1961, Vol. 3, p. 2612). The same also occurs when the carboxy group is activated, as is necessary for the preparation of homoserineamides.
Although it is possible to react also N-acylhomoserine-lactones with alkylamines and amino acid esters or amino acid salts to form the corresponding amides (Sheradsky et al., J. Org. Chem. 1961, 26, 2710), the reaction requires either very long reaction times or relatively high temperatures. For that reason, this method has not been used for the preparation of complex, optionally optically active compounds.
For the preparation of homoserineamides there are used homoserine derivatives in which the hydroxy function is protected by a suitable group. Hitherto, that was achieved either by a trityl group (Barlos et al., J. Chem. Soc., Chem. Commun. 1986, 1259), by mono- or di-methoxytrityl groups (Beltran et al., Lett. Pept. Sci. 1997, 4, 147), tert.-butyldimethylsilyl group (WO 97/46248) or benzyl groups (Cornille et al., J. Am. Chem. Soc. 1995, 117, 909). The disadvantage of those protecting groups is that they either require expensive chemicals or can be introduced only in a complicated manner.
O-Acyl compounds could be simple and inexpensive protecting groups. However, the problem with those compounds is that they very rapidly undergo an O- greater than N-acyl shift under basic conditions, with formation of the corresponding N-acylhomoserines. Furthermore, for the preparation of O-acetylhomoserine there has hitherto been described only the reaction of homoserine with acyl anhydrides in perchloric acid which, on account of the explosive tendency of perchlorates, appears to be very disadvantageous and unsuitable for larger batches. The yields are only 51% at the most (Nagani et al., J. Biol.
Chem. 1967, 242, 3884).
Accordingly, the object of the present invention is to provide a further process for the preparation of xcex3-lactams of the general formula I which can advantageously be carried out on an industrial scale, that is to say which avoids the use of critical substances and expensive reagents as far as possible. Within the context of the invention, critical substances are to be understood as being compounds which, when used on a large scale, give rise to particular risks as regards environmental pollution or health and safety at work.
Another object of the present invention is to provide a process which allows the xcex3-lactams of the general formula I to be prepared without formation of the foul-smelling dimethyl sulfide.
A further object of the invention is to provide novel intermediates which can advantageously be used for the synthesis of the xcex3-lactams of the general formula I, and to indicate an advantageous use of those intermediates.
These and other objects, which are not explained in greater detail but which readily follow from the prior art in an obvious manner, are the subject of a process having the features of the characterising clause of claim 1. Advantageous developments of the process according to the invention are described in the sub-claims which are dependent on claim 1. Claims 26 to 34 achieve the object of providing novel intermediates. In claim 35 there is described an advantageous use of the intermediates.
By synthesising a compound of the general formula I and its salts 
wherein
R1 may represent H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C2-C8)-alkoxyalkyl, (C1-C8)-acyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C3-C7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, N-bonded amino acid or peptide residue,
R2 may represent H, (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C2-C8)-alkoxyalkyl, which are optionally linear or branched and may be mono- or poly-substituted by halogens, by radicals containing N, O, P, S atoms, (C3-C7)-cycloalkyl, which may be saturated or unsaturated and mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms, and/or may contain hetero atoms such as N, O, P, S in the ring, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, heteroaryl, such as furyl, pyrrolyl, pyridyl, heteroaralkyl, such as furfuryl, pyrrolylmethyl, pyridylmethyl, furylethyl, pyrrolylethyl, pyridylethyl, wherein the rings just mentioned may optionally be mono- or poly-substituted by linear or branched (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl, by halogens, by radicals containing N, O, P, S atoms,
R3 may represent H, ClCO, (C1-C8)-acyl, which may optionally be linear or branched, a C-bonded amino acid or peptide residue or a conventional peptide-protecting group such as, for example, formyl, carbamoyl, benzyloxycarbonyl, tert.-butyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl, by cyclising derivatives of the general formula II 
wherein R1, R2, R3 are as defined above and X represents an element from the group halogen, sulfonic acid ester, the desired compounds of the general formula I are obtained in good yields in a very simple and nevertheless advantageous manner, the process according to the invention being predestined for a large-scale industrial process owing to the fact that the starting materials necessary for the synthesis are relatively inexpensive, the reaction is simple to perform, the yields are good, and dangerous or foul-smelling reagents are not used.
Within the context of the process according. to the invention, a sulfonic acid radical X is to be understood as being any radical derived from a sulfonic acid of the structure HOSO3Rxe2x80x2, wherein Rxe2x80x2 in this connection represents a linear or branched (C1-C8)-alkyl radical or an aryl radical which may optionally be substituted by one or more (C1-C8)-alkyl radicals. The mentioned radicals may optionally be substituted by one or more elements from the group halogen, preferably Cl or F.
The above-described cyclisation may advantageously be carried out under basic conditions, it being possible to use as the base preferably an alkali hydroxide. The use of aqueous alkali hydroxide solution is especially preferred, and very special preference is given to the use of sodium hydroxide solution for the cyclisation. Compounds of the general formula II that can advantageously be used for the cyclisation possess a sulfonic acid ester as the leaving group X, and the use of the so-called mesyl (OSO3Me) group is especially preferred.
This process can be applied very especially to compounds of the general formula II wherein R1 is a p-cyanophenyl or p-carbamoylphenyl radical, while R2 is advantageously H and R3=benzyloxycarbonyl.
The cyclisation can be carried out at temperatures of from xe2x88x9220xc2x0 C. to 100xc2x0 C. Temperatures of from 0xc2x0 C. to 50xc2x0 C. are preferably employed in the cyclisation, very especially temperatures of from 10xc2x0 C. to 30xc2x0 C.
The synthesis of the compounds of the general formula I can preferably and extremely simply be accomplished from compounds of the general formula II, if II is reacted to form I without being isolated beforehand.
The compounds of the general formula II can advantageously be prepared from derivatives of the general formula III 
wherein R1, R2, R3 are as defined above. The compounds of the general formula III are preferably not isolated before being processed further to form compounds of formula II.
The compounds of formula III, in turn, are very especially preferably prepared from compounds of the general formula IV 
wherein R1, R2, R3 are as defined above and R4 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C1-C8)-alkoxy, (C2-C8)-alkenyloxy, which are optionally linear or branched and are optionally substituted by one or more halogen atoms, aryl, such as phenyl or naphthyl, aralkyl, such as benzyl or phenethyl, arylalkyloxy, such as benzyloxy.
In principle, any processes for hydrolysis known to the person skilled in the art can be used for the above-mentioned conversion. Advantageously, however, compounds of the general formula IV can be converted into compounds of the general formula III by aminolysis. Special preference is given in this connection to the use of ammonia as the amine; very especially preferably, ammonia can be employed in the form of its aqueous solution.
The compound of the general formula IV, in turn, can advantageously be prepared from compounds of the general formula V 
wherein R2, R31, R4 are as defined above and R5 represents H, or wherein R3 and R5 are bonded together via a Cxe2x95x90O group to form a ring. Before they are reacted to form compounds of the general formula IV, compounds of the general formula V wherein R5 is H can be activated preferably by means of acid chlorides (analogously to Houben-Weyl, Volume 15, Part 2, p. 169 ff). Compounds of the general formula V wherein R3 and R5 are bonded together via a Cxe2x95x90O group to form a ring can advantageously be converted into compounds of the general formula IV wherein R3 represents H.
According to the invention, the compounds of the general formula V can advantageously be prepared from the acid addition salts of the general formula VI 
wherein R2, R4 are as defined above and Y"THgr" is the corresponding base of an inorganic acid, by reaction with an acylating reagent derived from R3. Within the scope of the invention, an inorganic acid is to be understood as being an acid whose pKa value is less than 2.5, such as, for example, HCl, HBr, H2SO4, H3PO4. Phosgene can preferably be used as the acylating reagent. In that case, compounds of the general formula V wherein R3 and R5 are bonded together via a Cxe2x95x90O group to form a ring are obtained. Alternatively, compounds of the general formula VI can be obtained by reaction with acylating reagents from the group of the organic anhydrides, such as, for example, di-tert.-butyl pyrocarbonate, of the activated esters, such as, for example, trifluoroacetic acid ester, acetic acid hydroxysuccinimide ester, or of the halocarbonic esters, such as, for example, benzyloxycarbonyl chloride, allyloxycarbonyl chloride or tert.-butyloxycarbonyl fluoride. The above-described acylation can preferably take place in aqueous solution at a pH of from 4 to 9; it is especially preferred to maintain a pH range of from 6.5 to 7.5 in that reaction. The acylation to form compounds of the general formula V wherein R5 is H can, however, also be carried out in organic solvents in the presence of a tertiary base. Triethylamine may advantageously be used as the tertiary base.
The acid addition salt of the general formula VI, in turn, can preferably be prepared from compounds of the general formula VII 
wherein R2 is as defined above. The reaction can take place in a mixture of a carboxylic acid R4COOH and the carboxylic acid chloride or bromide R4COCl or R4COBr, respectively, wherein R4 is as defined above. For that reaction it is advantageous first to mix together the appropriate carboxylic acid R4COOH and the corresponding carboxylic acid halide R4COHal and then to add the compound of the general formula VII to that mixture. The above-mentioned process is advantageously carried out at a temperature of from xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably from xe2x88x9210xc2x0 C. to 20xc2x0 C. and especially from xe2x88x925xc2x0 C. to 10xc2x0 C.
Another preferred variant for preparing the compound of the general formula V consists in reacting compounds of the general formula VIII 
wherein the radicals R2, R3 may be as defined above and R5 represents H, with the reagent R4COZ, wherein R4 is as defined above and Z represents an activating radical. The activating radical Z may in principle be any radical known to the person skilled in the art for that purpose, such as, for example, hydroxysuccinimide, hydroxybenzotriazole, R4CO2, halogen (The Chemical Synthesis of Peptides, J. Jones, Oxford Press 1991, p. 42 ff). For the acylation of the OH function of formula VIII there are preferably used compounds in which the activating radical Z corresponds to a halogen. In that case, the reaction is very especially preferably carried out in the carboxylic acid corresponding to the carboxylic acid halide as solvent. Especially preferred halides are the chlorides or bromides of the carboxylic acid. Very special preference is given to the embodiment in which the inorganic acid formed in the acylation is buffered by addition of the sodium-salt of the corresponding carboxylic acid used as solvent.
In a further aspect of the present invention, advantageous novel intermediates of the general formulae V, IV and II and their salts are provided 
wherein R1, R2, R3, R4, R5 are as defined above, wherein in formula V, when R2 is H, R3 may not be H. Preference is given to compounds in which R2 is hydrogen, R3 is a benzyloxycarbonyl, tert.-butyloxycarbonyl or tri-fluoroacetyl radical, R4 is a methyl radical and R5 is hydrogen, or in which R3 and R5 are bonded together via a Cxe2x95x90O group to form a ring. X is preferably a halogen or a sulfonic acid ester, very especially preferably an OSO3Me group. R1 is very especially preferably p-cyanophenyl or p-carbamoylphenyl.
The advantageous compounds of the general formulae V, IV and II are used according to the invention for the preparation of intermediates of biologically active substances.
The present invention is explained again in the scheme below: 
The cyclisation of II to I is an intramolecular nucleophilic substitution. In principle, any variant known to the person skilled in the art may be employed for that reaction. However, a number of subsidiary products, such as, for example, the removal or substitution of the leaving group, are to be expected in that reaction. For that reason it was very surprising that it was possible to find for the cyclisation, with the choice of leaving groups X, conditions that permit the use of a relatively strong basexe2x80x94in this case sodium hydroxidexe2x80x94in the presence of a polar protic, cation-stabilising solventxe2x80x94in this case waterxe2x80x94and nevertheless allow the reaction to proceed as selectively as possible. Those very inexpensive, uncritical reagents, which can readily be used for a large-scale process, are clearly to be preferred over other conditions from the prior art for the intramolecular substitution (dimethyl sulfide is not formed, sodium hydride is not used, no expensive reagents and solvents are required). A further advantage of those preferred reaction conditions is that the optical activity of enantiomerically enriched starting compounds is maintained virtually completely under the conditions according to the invention.
In the above-described reaction there are preferably used derivatives of II that contain the p-cyanophenyl or p-carbamoylphenyl group as the radical R1, H as R2, and a benzyloxycarbonyl radical as R3. They yield advantageous compounds for the preparation of pharmaceuticals, as described, for example, in WO 94/22820.
The preparation of the compounds of formula II from III can be carried out analogously to processes known from the literature. It is, however, preferred to form a sulfonic acid ester from III and sulfonic acid chloride, which ester can advantageously be reacted further in the manner indicated above, without being isolated as an intermediate, to form I. Special preference is given to the use of the mesyl (OSO3Me) group, which can be introduced using mesyl chloride and triethylamine as base. It is astonishing that under the preferred reaction conditions according to the invention it is not the hydrolysis of the sulfonic acid ester II but the cyclisation that is the main reaction. That was not foreseeable. It is also especially advantageous that the compounds of the general formula II do not have to be isolated before they are reacted to form I. They are formed and then preferably reacted in situ.
The preparation of the compounds of the general formula III from the compounds of the general formula IV can be carried out by acid or basic hydrolysis of the O-acyl group. Under those conditions, however, partial hydrolysis, for example of the N-acyl group which may be present and of the amide bond, may occur. Under the preferred hydrolysis variant, therefore, the removal of the O-acyl group is carried out by aminolysis. Ammonia is especially preferably used for that purpose, very especially preferably its aqueous solution. Under those conditions, the O-acyl group is removed selectively.
According to the invention it is also not necessary to isolate the compounds of the general formula III. They can also be reacted directly to form compounds of the general formula II. For the present process it is, therefore, extremely advantageous to select a process variant in which, starting from derivatives of the general formula IV to the end product of the general formula I, no intermediate stage is isolated intermediately. Nevertheless, the derivatives of the general formula I are obtained in good to very good yields and with a very high degree of purity. That was surprising and could in no way be foreseen; it is, however, all the more advantageous for a large-scale process since the very cost-intensive handling of isolated intermediate products can be reduced to a minimum.
There may be used as solvents for the conversion of IIIxe2x86x92II any organic solvents that are inert under the given conditions. Special preference is given to ethers, such as, for example, methyl tert.-butyl ether, tetrahydrofuran, dimethoxyethane, dioxane, hydrocarbons, such as, for example, hexane, cyclohexane, toluene, ketones, such as,. for example, acetone, diethyl ketone, methyl isobutyl ketone, and carboxylic acid alkyl esters, such as, for example, ethyl acetate, isopropyl acetate, n-butyl acetate. Very special preference is given to organic solvents that form a low-boiling azeotrope with water, such as, for example, toluene, methyl isobutyl ketone or n-butyl acetate.
Compounds of formula IV, in turn, can preferably be obtained from derivatives V. In the case where-the radicals R3 and R5 are bonded together via a Cxe2x95x90O group to form a ring, that is to say an N-carboxylic acid anhydride of the derivative in question is present, the carboxy function of the homoserine derivative does not have to be activated for the coupling. The derivatives are then simply reacted with the chosen amine, yielding compounds of formula IV wherein R3 is H. The latter can be converted into the corresponding N-acyl compounds in accordance with processes known from the literature by reaction with an acylating reagent derived from R3.
In the case where R5=H, the carboxy function is activated before coupling with the amine. That is effected by methods of peptide chemistry known to the person skilled in the art (Houben-Weyl, Volume 15, 2nd part), such as, for example, via mixed anhydrides, activated esters, etc. Reaction with an acid chloride, such as, for example, pivaloyl chloride, to form the mixed anhydride is, however, preferred.
The compounds of the general formula V according to the invention can be obtained from homoserine derivatives such as VII by two different methods. Either VII is first acylated at the oxygen to form VI and then processed further at the nitrogen by N-acylation to form V, or compounds of the general formula VIII, which are obtainable from VII by N-acylation, are converted into V by O-acylation.
The N-acylation to form the homoserine derivative VIII can be carried out analogously to that of other amino acids (Houben-Weyl, Volume 15, Part 1 and Part 2). In principle there may be used as the acylating reagents any acylating reagents derived from R3, such as amino-protecting reagents, C-terminal activated amino acids or peptides.
In the isolation of the N-acylhomoserines of formula VIII there was, however, the problem that those compounds, as the free acid, are very unstable and readily cyclise to form the corresponding lactones. That cyclisation is catalysed by acids and, moreover, always occurs when the acid function is activated. It takes place also in the reaction with the activated acid derivative R4COZ under the basic conditions which are otherwise customary for acylations. However, if the O-acylation is carried out in, as solvent, the carboxylic acid R4COOH corresponding to the reagent R4COZ used for the O-acylation, then the desired derivatives V are obtained almost exclusively. Special preference is given to the use of Cl for Z. A base is optionally and advantageously used to buffer the acid that forms during the reaction. The sodium salt of the carboxylic acid used as solvent is advantageously added as the base. The subsidiary product, the lactone, which is also formed in that process but to a lesser extent can be separated from the product mixture in a simple manner by extraction and, after ring-opening, is available for the reaction again.
In the second variant, the O-acylation to form derivatives VI is carried out according to the invention in a medium that helps to prevent the N-acylation, since that would be the more rapid reaction. The reaction is, therefore, preferably carries out in a carboxylic acid such as R4COOH, to which the appropriate corresponding carboxylic acid halide, preferably carboxylic acid chloride, has previously been added. When the homoserine derivative VII is subsequently added, protection of the amino function of VII takes place by protonation as a result of the strong inorganic acid that forms in the solvent, and acylation of the hydroxy function preferentially occurs. The acid addition salt of the hydroxy-protected homoserine VI is therefore obtained as the product. The use of the dangerous perchloric acid, as is known from the prior art, is thus avoided. Furthermore, the yields in the process according to the invention are markedly better.
The further reaction of derivatives VI to form V can in principle be carried out by processes known to the person skilled in the art using an acylating reagent derived from R3, such as amino-protecting reagents, C-terminal activated amino acids, peptides, or using phosgene. There was the problem, however, that the O-acylhomoserines VI rapidly undergo an Oxe2x86x92N-acyl shift under basic conditions. According to the process of the invention, that can be avoided by maintaining the pH range, if the acylation is carried out in an aqueous medium, at from 3 to 9, preferably from 6 to 7.5. A further possibility is to react the O-acyl compounds VI in anhydrous solvents and triethylamine as base. For the reaction with phosgene, the acid addition salt VI can be used without addition of a base.
There come into consideration as linear or branched (C1-C8)-alkyl radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl or octyl, including all possible isomers of constitution. The linear or branched (C2-C8)-alkenyl radical includes all the substituents.listed above in connection with the (C1-C8)-alkyl radical with the exception of the methyl radical, at least one double bond being present in those radicals. The scope of (C2-C8)-alkynyl corresponds to that of (C2-C8)-alkenyl, but at least one triple bond must be present in that case. The radical (C1-C8)-alkoxy corresponds to the radical (C1-C8)-alkyl, with the proviso that it is bonded to the ring via an oxygen atom. (C2-C8)-Alkoxyalkyl radicals are radicals in which the alkyl chain is interrupted by at least one oxygen function, wherein two oxygens may not be bonded together. The number of carbon atoms indicates the total number of carbon atoms contained in the radical. (C2-C8)-Alkenyloxy is to be understood as meaning radicals such as (C2-C8)-alkoxy that have at least one C-C double bond. Radicals containing N, O, P, S atoms are especially alkyl, alkenyl, alkynyl radicals of the above-mentioned type that have one or more of those hetero atoms in their chain or that are bonded to the molecule via one of those hetero atoms. (C3-C7)-Cycloalkyl is to be understood as being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radicals.
There are suitable as halogens fluorine, chlorine, bromine and iodine.
An N-bonded amino acid or peptide residue is to be understood as being a compound in which the molecule in question is bonded via its N atom to the xcex1-carbon atom of a carboxylic acid derived from an amino acid, which carboxylic acid may be part of a peptide residue.
A C-bonded amino acid or peptide residue is to be understood as being a compound in which the molecule in question is bonded via its N atom to the carbon atom of the carboxyl group of an amino acid, which may be part of a peptide.
(C1-C8)-Acyl is to be understood as being an alkyl radical having from one to eight carbon atoms, which may be linear or branched, that is to say which likewise includes all the possible isomers of constitution, and which is bonded to the molecule via a Cxe2x95x90O function.
Within the scope of the invention, compounds having a stereogenic centre mean racemates as well as the enantiomeric antipodes of those structures. However, for the process according to the invention it is preferred to use enantiomerically enriched homoserine derivatives of the general formula VII. Thus, when the enantiomerically enriched starting materials (D or L) are used, the ID enantiomerically enriched products of the general formulae V and I (D or L) are obtained with virtually complete stereoconservation.
Salts are to be understood as being ionic addition compounds from strong acids such as HCl , HBr, H2SO4, H3PO4, CF3COOH, p-toluenesulfonic acid, methanesulfonic acid and the molecule in question.